title: Lysosome-mediated processing of chromatin in senescence.
abstract: Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C-negative, but strongly γ-H2AX-positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression.
authors.affiliation: Institute of Cancer Sciences, CR-UK Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, Scotland, UK.
authors.forename: Andre
authors.initials: A
authors.lastname: Ivanov
authors.forename: Jeff
authors.initials: J
authors.lastname: Pawlikowski
authors.forename: Indrani
authors.initials: I
authors.lastname: Manoharan
authors.forename: John
authors.initials: J
authors.lastname: van Tuyn
authors.forename: David M
authors.initials: DM
authors.lastname: Nelson
authors.forename: Taranjit Singh
authors.initials: TS
authors.lastname: Rai
authors.forename: Parisha P
authors.initials: PP
authors.lastname: Shah
authors.forename: Graeme
authors.initials: G
authors.lastname: Hewitt
authors.forename: Viktor I
authors.initials: VI
authors.lastname: Korolchuk
authors.forename: Joao F
authors.initials: JF
authors.lastname: Passos
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
mesh_terms: D001343:Autophagy; D001692:Biological Transport; D002463:Cell Membrane Permeability; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D003593:Cytoplasm / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism; D059748:Proteolysis; D059008:Time-Lapse Imaging
chemical_list: D002843:Chromatin; D006657:Histones; C478221:LAMB1 protein, human; D007797:Laminin; C084098:laminin A